(Ph. Eur. monograph 1555)
C20H30N2O3S2 410.6 66104-23-2
Action and use
Dopamine receptor agonist; treatment of Parkinson’s disease.
DEFINITION
(6aR,9R,10aR)-9-[(Methylsulfanyl)methyl]-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline monomethanesulfonate.
Content
97.5 per cent to 102.0 per cent (dried substance).
PRODUCTION
It is considered that alkyl methanesulfonate esters are genotoxic and are potential impurities in pergolide mesilate. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general methods 2.5.37.
Methyl, ethyl and isopropyl methanesulfonate in methanesulfonic acid, 2.5.38. Methyl, ethyl and isopropyl methanesulfonate in active substances and 2.5.39. Methanesulfonyl chloride in methanesulfonic acid are available to assist manufacturers.
CHARACTERS
Appearance
White or almost white, crystalline powder.
Solubility
Slightly soluble in water, sparingly soluble in methanol, slightly soluble in ethanol (96 per cent) and in methylene chloride, very slightly soluble in acetone.
IDENTIFICATION
A. Specific optical rotation (2.2.7): -23 to -17 (dried substance).
Dissolve 0.25 g in dimethylformamide R and dilute to 25.0 mL with the same solvent.
B. Infrared absorption spectrophotometry (2.2.24).
Preparation: Discs.
Comparison: pergolide mesilate CRS.
TESTS
Related substances
Liquid chromatography (2.2.29).
Test solution: Dissolve 30.0 mg of the substance to be examined in methanol R and dilute to 10.0 mL with the same solvent.
Reference solution (a): Dilute 1.0 mL of the test solution to 100.0 mL with methanol R. Dilute 1.0 mL of this solution to 10.0 mL with methanol R.
Reference solution (b): Dissolve 10 mg of 4,4′-dimethoxybenzophenone R in methanol R and dilute to 10 mL with the same solvent. To 1 mL of the solution add 2 mL of the test solution and dilute to 100 mL with methanol R. Dilute 1 mL of this solution to 10 mL with methanol R.
Column:
— size: l = 0.25 m, Ø = 4.6 mm;
— stationary phase: base-deactivated octadecylsilyl silica gel for chromatography R (5 μm);
— temperature: 40 °C.
Mobile phase:
— mobile phase A: mix 5.0 mL of morpholine for chromatography R with 995 mL of water R and adjust to pH 7.0 with phosphoric acid R; use within 24 h;
— mobile phase B: acetonitrile R, methanol R, tetrahydrofuran R (1:1:1 V/V/V);
| Time (min) |
Mobile phase A (per cent V/V) |
Mobile phase B (per cent V/V) |
| 0 – 35 | 70 → 0 | 30 → 100 |
| 35 – 40 | 0 → 70 | 100 → 30 |
| 40 – 50 | 70 | 30 |
Flow rate: 1 mL/min.
Detection: Spectrophotometer at 280 nm.
Injection: 20 μL.
System suitability: Reference solution (b):
— resolution: minimum 2.0 between the peaks due to 4,4′-dimethoxybenzophenone (1 peak) and pergolide (2 peak).
Limits:
— impurity A: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent);
— total: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.5 per cent);
— disregard limit: 0.2 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.02 per cent).
Loss on drying (2.2.32)
Maximum 0.5 per cent, determined on 1.000 g by drying in vacuo at 105 °C for 1 h.
Sulfated ash (2.4.14)
Maximum 0.1 per cent, determined on 1.0 g.
ASSAY
Liquid chromatography (2.2.29).
Solution A: Dissolve 5.0 mg of DL-methionine R in 500 mL of 0.01 M hydrochloric acid. Add 500 mL of methanol R and mix.
Test solution: Dissolve 65.0 mg of the substance to be examined in solution A and dilute to 100.0 mL with solution A.
Dilute 10.0 mL of this solution to 100.0 mL with solution A.
Reference solution: Dissolve 65.0 mg of pergolide mesilate CRS in solution A and dilute to 100.0 mL with solution A.
Dilute 10.0 mL of this solution to 100.0 mL with solution A.
Column:
— size: l = 0.25 m, Ø = 4.6 mm;
— stationary phase: base-deactivated octylsilyl silica gel for chromatography R (5 μm);
— temperature: 40 °C.
Mobile phase: Mix 1 volume of acetonitrile R, 1 volume of methanol R and 2 volumes of a mixture prepared as follows: dissolve 2.0 g of sodium octanesulfonate R in water R, add 1.0 mL of anhydrous acetic acid R and dilute to 1000 mL with water R.
Flow rate: 1 mL/min.
Detection: Spectrophotometer at 280 nm.
Injection: 20 μL.
Retention time: Pergolide = about 9 min.
System suitability: Reference solution:
— symmetry factor: maximum 1.5 for the peak due to pergolide.
Calculate the percentage content of C20H30N2O3S2 from the assigned content of pergolide mesilate CRS.
STORAGE
Protected from light.
IMPURITIES
Specified impurities A.
Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use) B.
A. (6aR,9R,10aR)-9-[(methylsulfinyl)methyl]-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline (pergolide sulfoxide),
B. (6aR,9R,10aR)-9-[(methylsulfonyl)methyl]-7-propyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline (pergolide sulfone).
